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Article: Genome-wide analysis of alternative pre-mRNA splicing.

Ben-Dov, Claudia / Hartmann, Britta / Lundgren, Josefin / Valcárcel, Juan

2007 Volume 283, Issue 3, Page(s) 1229–1233

Abstract: Alternative splicing of mRNA precursors allows the synthesis of multiple mRNAs from a single primary transcript, significantly expanding the information content and regulatory possibilities of higher eukaryotic genomes. High-throughput enabling ... ...

Abstract	Alternative splicing of mRNA precursors allows the synthesis of multiple mRNAs from a single primary transcript, significantly expanding the information content and regulatory possibilities of higher eukaryotic genomes. High-throughput enabling technologies, particularly large-scale sequencing and splicing-sensitive microarrays, are providing unprecedented opportunities to address key questions in this field. The picture emerging from these pioneering studies is that alternative splicing affects most human genes and a significant fraction of the genes in other multicellular organisms, with the potential to greatly influence the evolution of complex genomes. A combinatorial code of regulatory signals and factors can deploy physiologically coherent programs of alternative splicing that are distinct from those regulated at other steps of gene expression. Pre-mRNA splicing and its regulation play important roles in human pathologies, and genome-wide analyses in this area are paving the way for improved diagnostic tools and for the identification of novel and more specific pharmaceutical targets.
MeSH term(s)	Alternative Splicing/genetics ; Animals ; Disease ; Genome, Human/genetics ; Humans ; RNA Precursors/genetics
Chemical Substances	RNA Precursors
Language	English
Publishing date	2007-11-16
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1074/jbc.R700033200
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Article ; Online: CPEB1 coordinates alternative 3'-UTR formation with translational regulation.

Bava, Felice-Alessio / Eliscovich, Carolina / Ferreira, Pedro G / Miñana, Belen / Ben-Dov, Claudia / Guigó, Roderic / Valcárcel, Juan / Méndez, Raúl

Nature

2013 Volume 495, Issue 7439, Page(s) 121–125

Abstract: More than half of mammalian genes generate multiple messenger RNA isoforms that differ in their 3' untranslated regions (3' UTRs) and therefore in regulatory sequences, often associated with cell proliferation and cancer; however, the mechanisms ... ...

Abstract	More than half of mammalian genes generate multiple messenger RNA isoforms that differ in their 3' untranslated regions (3' UTRs) and therefore in regulatory sequences, often associated with cell proliferation and cancer; however, the mechanisms coordinating alternative 3'-UTR processing for specific mRNA populations remain poorly defined. Here we report that the cytoplasmic polyadenylation element binding protein 1 (CPEB1), an RNA-binding protein that regulates mRNA translation, also controls alternative 3'-UTR processing. CPEB1 shuttles to the nucleus, where it co-localizes with splicing factors and mediates shortening of hundreds of mRNA 3' UTRs, thereby modulating their translation efficiency in the cytoplasm. CPEB1-mediated 3'-UTR shortening correlates with cell proliferation and tumorigenesis. CPEB1 binding to pre-mRNAs not only directs the use of alternative polyadenylation sites, but also changes alternative splicing by preventing U2AF65 recruitment. Our results reveal a novel function of CPEB1 in mediating alternative 3'-UTR processing, which is coordinated with regulation of mRNA translation, through its dual nuclear and cytoplasmic functions.
MeSH term(s)	3' Untranslated Regions/genetics ; Alternative Splicing/genetics ; Cell Cycle Proteins/genetics ; Cell Nucleus/metabolism ; Cell Proliferation ; Cell Transformation, Neoplastic ; Cytoplasm/metabolism ; HeLa Cells ; Humans ; Models, Genetic ; Nuclear Proteins/metabolism ; Poly A/genetics ; Poly A/metabolism ; Poly-ADP-Ribose Binding Proteins ; Polyadenylation/genetics ; Protein Biosynthesis/genetics ; RNA, Messenger/genetics ; RNA, Messenger/metabolism ; Ribonucleoproteins/metabolism ; Splicing Factor U2AF ; Transcription Factors/metabolism ; mRNA Cleavage and Polyadenylation Factors/metabolism
Chemical Substances	3' Untranslated Regions ; BUB3 protein, human ; CPEB1 protein, human ; Cell Cycle Proteins ; Nuclear Proteins ; Poly-ADP-Ribose Binding Proteins ; RNA, Messenger ; Ribonucleoproteins ; Splicing Factor U2AF ; Transcription Factors ; U2AF2 protein, human ; mRNA Cleavage and Polyadenylation Factors ; Poly A (24937-83-5)
Language	English
Publishing date	2013-02-24
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	120714-3
ISSN	1476-4687 ; 0028-0836
ISSN (online)	1476-4687
ISSN	0028-0836
DOI	10.1038/nature11901
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Article: Genome-wide Analysis of Alternative Pre-mRNA Splicing

Ben-Dov, Claudia / Hartmann, Britta / Lundgren, Josefin / Valcárcel, Juan

Journal of biological chemistry. 2008 Jan. 18, v. 283, no. 3

2008

Abstract	Alternative splicing of mRNA precursors allows the synthesis of multiple mRNAs from a single primary transcript, significantly expanding the information content and regulatory possibilities of higher eukaryotic genomes. High-throughput enabling technologies, particularly large-scale sequencing and splicing-sensitive microarrays, are providing unprecedented opportunities to address key questions in this field. The picture emerging from these pioneering studies is that alternative splicing affects most human genes and a significant fraction of the genes in other multicellular organisms, with the potential to greatly influence the evolution of complex genomes. A combinatorial code of regulatory signals and factors can deploy physiologically coherent programs of alternative splicing that are distinct from those regulated at other steps of gene expression. Pre-mRNA splicing and its regulation play important roles in human pathologies, and genome-wide analyses in this area are paving the way for improved diagnostic tools and for the identification of novel and more specific pharmaceutical targets.
Language	English
Dates of publication	2008-0118
Size	p. 1229-1233.
Publishing place	American Society for Biochemistry and Molecular Biology
Document type	Article
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
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Article: Analysis of the highly efficient pre-mRNA processing region HX1 of Trypanosoma cruzi.

Ben-Dov, Claudia P / Levin, Mariano J / Vázquez, Martín P

Molecular and biochemical parasitology

2005 Volume 140, Issue 1, Page(s) 97–105

Abstract: Gene expression in trypanosomes is controlled mainly by post-transcriptional processes. This study was designed to analyse HX1, one of the TcP2beta upstream intergenic regions. It is an efficient pre-mRNA processing region that has been widely and ... ...

Abstract	Gene expression in trypanosomes is controlled mainly by post-transcriptional processes. This study was designed to analyse HX1, one of the TcP2beta upstream intergenic regions. It is an efficient pre-mRNA processing region that has been widely and successfully used in Trypanosoma cruzi transfection vectors. Herein we compared its performance with other regions within the same locus, and we identified the sequence elements responsible for the HX1 efficiency in trans-splicing and protein synthesis. Our mutational analysis showed the flexibility of the branch point site selection for HX1 trans-splicing process. We demonstrated also that its 12 nt 5'UTR sequence contributes to both trans-splicing and translation efficiency. The natural insertion of the repetitive element short interspersed repetitive element (SIRE) in one of the HX1 polypyrimidine tracts decreases the translated protein level by 40%. In this report, we demonstrated that this reduction is a consequence of a decrease of five-fold in the level of processed mRNA balanced by an increased efficiency of translation due to the inclusion of a 38 nt SIRE specific sequence in the 5'UTR of the mRNA.
MeSH term(s)	5' Untranslated Regions ; Animals ; Base Sequence ; DNA, Intergenic ; Molecular Sequence Data ; Protein Biosynthesis ; Protozoan Proteins/biosynthesis ; Protozoan Proteins/genetics ; RNA, Messenger/biosynthesis ; RNA, Protozoan/genetics ; Repetitive Sequences, Nucleic Acid ; Ribosomal Proteins/biosynthesis ; Ribosomal Proteins/genetics ; Trans-Splicing ; Trypanosoma cruzi/genetics
Chemical Substances	5' Untranslated Regions ; DNA, Intergenic ; Protozoan Proteins ; RNA, Messenger ; RNA, Protozoan ; Ribosomal Proteins
Language	English
Publishing date	2005-03
Publishing country	Netherlands
Document type	Comparative Study ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	756166-0
ISSN	1872-9428 ; 0166-6851
ISSN (online)	1872-9428
ISSN	0166-6851
DOI	10.1016/j.molbiopara.2005.01.001
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Article ; Online: Unconstrained mining of transcript data reveals increased alternative splicing complexity in the human transcriptome.

Mollet, I G / Ben-Dov, Claudia / Felício-Silva, Daniel / Grosso, A R / Eleutério, Pedro / Alves, Ruben / Staller, Ray / Silva, Tito Santos / Carmo-Fonseca, Maria

Nucleic acids research

2010 Volume 38, Issue 14, Page(s) 4740–4754

Abstract: Mining massive amounts of transcript data for alternative splicing information is paramount to help understand how the maturation of RNA regulates gene expression. We developed an algorithm to cluster transcript data to annotated genes to detect ... ...

Abstract	Mining massive amounts of transcript data for alternative splicing information is paramount to help understand how the maturation of RNA regulates gene expression. We developed an algorithm to cluster transcript data to annotated genes to detect unannotated splice variants. A higher number of alternatively spliced genes and isoforms were found compared to other alternative splicing databases. Comparison of human and mouse data revealed a marked increase, in human, of splice variants incorporating novel exons and retained introns. Previously unannotated exons were validated by tiling array expression data and shown to correspond preferentially to novel first exons. Retained introns were validated by tiling array and deep sequencing data. The majority of retained introns were shorter than 500 nt and had weak polypyrimidine tracts. A subset of retained introns matching small RNAs and displaying a high GC content suggests a possible coordination between splicing regulation and production of noncoding RNAs. Conservation of unannotated exons and retained introns was higher in horse, dog and cow than in rodents, and 64% of exon sequences were only found in primates. This analysis highlights previously bypassed alternative splice variants, which may be crucial to deciphering more complex pathways of gene regulation in human.
MeSH term(s)	Algorithms ; Alternative Splicing ; Animals ; Base Composition ; Base Sequence ; Conserved Sequence ; Data Mining ; Exons ; Gene Expression Profiling ; Genomics/methods ; Humans ; Introns ; Mice ; Oligonucleotide Array Sequence Analysis ; Protein Isoforms/genetics ; RNA, Messenger/chemistry ; RNA, Untranslated/metabolism ; Sequence Alignment
Chemical Substances	Protein Isoforms ; RNA, Messenger ; RNA, Untranslated
Language	English
Publishing date	2010-04-12
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	186809-3
ISSN	1362-4962 ; 1362-4954 ; 0301-5610 ; 0305-1048
ISSN (online)	1362-4962 ; 1362-4954
ISSN	0301-5610 ; 0305-1048
DOI	10.1093/nar/gkq197
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Article: Alternative splicing microarrays reveal functional expression of neuron-specific regulators in Hodgkin lymphoma cells.

Relógio, Angela / Ben-Dov, Claudia / Baum, Michael / Ruggiu, Matteo / Gemund, Christine / Benes, Vladimir / Darnell, Robert B / Valcárcel, Juan

The Journal of biological chemistry

2004 Volume 280, Issue 6, Page(s) 4779–4784

Abstract: Alternative splicing provides a versatile mechanism of gene regulation, which is often subverted in disease. We have used customized oligonucleotide microarrays to interrogate simultaneously the levels of expression of splicing factors and the patterns ... ...

Abstract	Alternative splicing provides a versatile mechanism of gene regulation, which is often subverted in disease. We have used customized oligonucleotide microarrays to interrogate simultaneously the levels of expression of splicing factors and the patterns of alternative splicing of genes involved in tumor progression. Analysis of RNAs isolated from cell lines derived from Hodgkin lymphoma tumors indicate that the relative abundance of alternatively spliced isoforms correlates with transformation and tumor grade. Changes in expression of regulators were also detected, and a subset sample was confirmed at the protein level. Ectopic expression of neuron-specific splicing regulatory proteins of the Nova family was observed in some cell lines and tumor samples, correlating with expression of a neuron-specific mRNA isoform of JNK2 kinase. This microarray design can help assess the role of alternative splicing in a variety of biological and medical problems and potentially serve as a diagnostic tool.
MeSH term(s)	Alternative Splicing ; Blotting, Western ; Cell Line, Tumor ; Cluster Analysis ; Cyclin-Dependent Kinase Inhibitor p16/chemistry ; DNA, Complementary/metabolism ; Databases as Topic ; Hodgkin Disease/metabolism ; Humans ; Mitogen-Activated Protein Kinase 9/metabolism ; Neurons/metabolism ; Oligonucleotide Array Sequence Analysis ; Protein Isoforms ; RNA/chemistry ; RNA/metabolism ; RNA, Messenger/metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Tumor Suppressor Protein p14ARF/chemistry
Chemical Substances	Cyclin-Dependent Kinase Inhibitor p16 ; DNA, Complementary ; Protein Isoforms ; RNA, Messenger ; Tumor Suppressor Protein p14ARF ; RNA (63231-63-0) ; Mitogen-Activated Protein Kinase 9 (EC 2.7.1.24)
Language	English
Publishing date	2004-11-16
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1074/jbc.M411976200
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Article ; Online: Expression of the human RNA-binding protein HuR in Trypanosoma brucei increases the abundance of mRNAs containing AU-rich regulatory elements.

Quijada, Luis / Guerra-Giraldez, Cristina / Drozdz, Maciej / Hartmann, Claudia / Irmer, Henriette / Ben-Dov, Claudia / Cristodero, Marina / Ding, Martina / Clayton, Christine

Nucleic acids research

2001 Volume 30, Issue 20, Page(s) 4414–4424

Abstract: The salivarian trypanosome Trypanosoma brucei infects mammals and is transmitted by tsetse flies. The mammalian 'bloodstream form' trypanosome has a variant surface glycoprotein coat and relies on glycolysis while the procyclic form from tsetse flies has ...

Abstract	The salivarian trypanosome Trypanosoma brucei infects mammals and is transmitted by tsetse flies. The mammalian 'bloodstream form' trypanosome has a variant surface glycoprotein coat and relies on glycolysis while the procyclic form from tsetse flies has EP protein on the surface and has a more developed mitochondrion. We show here that the mRNA for the procyclic-specific cytosolic phosphoglycerate kinase PGKB, like that for EP proteins, contains a regulatory AU-rich element (ARE) that destabilises the mRNA in bloodstream forms. The human HuR protein binds to, and stabilises, mammalian mRNAs containing AREs. Expression of HuR in bloodstream-form trypanosomes resulted in growth arrest and in stabilisation of the EP, PGKB and pyruvate, phosphate dikinase mRNAs, while three bloodstream-specific mRNAs were reduced in abundance. The synthesis and abundance of unregulated mRNAs and proteins were unaffected. Our results suggest that regulation of mRNA stability by AREs arose early in eukaryotic evolution.
MeSH term(s)	3' Untranslated Regions ; Adenine/analysis ; Animals ; Antigens, Surface ; Base Sequence ; ELAV Proteins ; ELAV-Like Protein 1 ; Gene Expression Regulation, Developmental ; Humans ; Molecular Sequence Data ; Phosphoglycerate Kinase/genetics ; Phosphoglycerate Kinase/metabolism ; Protozoan Proteins/biosynthesis ; RNA Stability ; RNA, Messenger/chemistry ; RNA, Messenger/metabolism ; RNA, Protozoan/chemistry ; RNA, Protozoan/metabolism ; RNA-Binding Proteins/genetics ; RNA-Binding Proteins/metabolism ; Regulatory Sequences, Nucleic Acid ; Trypanosoma brucei brucei/genetics ; Trypanosoma brucei brucei/growth & development ; Trypanosoma brucei brucei/metabolism ; Uracil/analysis
Chemical Substances	3' Untranslated Regions ; Antigens, Surface ; ELAV Proteins ; ELAV-Like Protein 1 ; ELAVL1 protein, human ; Protozoan Proteins ; RNA, Messenger ; RNA, Protozoan ; RNA-Binding Proteins ; Uracil (56HH86ZVCT) ; Phosphoglycerate Kinase (EC 2.7.2.3) ; Adenine (JAC85A2161)
Language	English
Publishing date	2001-02-06
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	186809-3
ISSN	1362-4962 ; 1362-4954 ; 0301-5610 ; 0305-1048
ISSN (online)	1362-4962 ; 1362-4954
ISSN	0301-5610 ; 0305-1048
DOI	10.1093/nar/gkf577
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Article: Protein phosphatase 1 binds to the RNA recognition motif of several splicing factors and regulates alternative pre-mRNA processing.

Novoyatleva, Tatyana / Heinrich, Bettina / Tang, Yesheng / Benderska, Natalya / Butchbach, Matthew E R / Lorson, Christian L / Lorson, Monique A / Ben-Dov, Claudia / Fehlbaum, Pascale / Bracco, Laurent / Burghes, Arthur H M / Bollen, Mathieu / Stamm, Stefan

Human molecular genetics

2007 Volume 17, Issue 1, Page(s) 52–70

Abstract: Alternative splicing emerges as one of the most important mechanisms to generate transcript diversity. It is regulated by the formation of protein complexes on pre-mRNA. We demonstrate that protein phosphatase 1 (PP1) binds to the splicing factor ... ...

Abstract	Alternative splicing emerges as one of the most important mechanisms to generate transcript diversity. It is regulated by the formation of protein complexes on pre-mRNA. We demonstrate that protein phosphatase 1 (PP1) binds to the splicing factor transformer2-beta1 (tra2-beta1) via a phylogenetically conserved RVDF sequence located on the RNA recognition motif (RRM) of tra2-beta1. PP1 binds directly to tra2-beta1 and dephosphorylates it, which regulates the interaction between tra2-beta1 and other proteins. Eight other proteins, including SF2/ASF and SRp30c, contain an evolutionary conserved PP1 docking motif in the beta-4 strand of their RRMs indicating that binding to PP1 is a new function of some RRMs. Reducing PP1 activity promotes usage of numerous alternative exons, demonstrating a role of PP1 activity in splice site selection. PP1 inhibition promotes inclusion of the survival of motoneuron 2 exon 7 in a mouse model expressing the human gene. This suggests that reducing PP1 activity could be a new therapeutic principle to treat spinal muscular atrophy and other diseases caused by missplicing events. Our data indicate that the binding of PP1 to evolutionary conserved motifs in several RRMs is the link between known signal transduction pathways regulating PP1 activity and pre-mRNA processing.
MeSH term(s)	Alternative Splicing ; Amino Acid Motifs ; Amino Acid Sequence ; Animals ; Base Sequence ; Binding Sites ; Cell Line ; Conserved Sequence ; Cyclic AMP Response Element-Binding Protein/chemistry ; Cyclic AMP Response Element-Binding Protein/genetics ; Cyclic AMP Response Element-Binding Protein/metabolism ; DNA Primers/genetics ; Evolution, Molecular ; Exons ; Humans ; Molecular Sequence Data ; Nerve Tissue Proteins/chemistry ; Nerve Tissue Proteins/genetics ; Nerve Tissue Proteins/metabolism ; Phylogeny ; Protein Phosphatase 1/metabolism ; RNA Precursors/metabolism ; RNA-Binding Proteins/chemistry ; RNA-Binding Proteins/genetics ; RNA-Binding Proteins/metabolism ; Recombinant Proteins/chemistry ; Recombinant Proteins/genetics ; Recombinant Proteins/metabolism ; SMN Complex Proteins ; Sequence Homology, Amino Acid ; Serine-Arginine Splicing Factors
Chemical Substances	Cyclic AMP Response Element-Binding Protein ; DNA Primers ; Nerve Tissue Proteins ; RNA Precursors ; RNA-Binding Proteins ; Recombinant Proteins ; SMN Complex Proteins ; TRA2B protein, human ; Serine-Arginine Splicing Factors (170974-22-8) ; Protein Phosphatase 1 (EC 3.1.3.16)
Language	English
Publishing date	2007-10-02
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1108742-0
ISSN	1460-2083 ; 0964-6906
ISSN (online)	1460-2083
ISSN	0964-6906
DOI	10.1093/hmg/ddm284
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Article ; Online: DNA damage regulates alternative splicing through inhibition of RNA polymerase II elongation.

Muñoz, Manuel J / Pérez Santangelo, M Soledad / Paronetto, Maria P / de la Mata, Manuel / Pelisch, Federico / Boireau, Stéphanie / Glover-Cutter, Kira / Ben-Dov, Claudia / Blaustein, Matías / Lozano, Juan J / Bird, Gregory / Bentley, David / Bertrand, Edouard / Kornblihtt, Alberto R

Cell

2009 Volume 137, Issue 4, Page(s) 708–720

Abstract: DNA damage induces apoptosis and many apoptotic genes are regulated via alternative splicing (AS), but little is known about the control mechanisms. Here we show that ultraviolet irradiation (UV) affects cotranscriptional AS in a p53-independent way, ... ...

Abstract	DNA damage induces apoptosis and many apoptotic genes are regulated via alternative splicing (AS), but little is known about the control mechanisms. Here we show that ultraviolet irradiation (UV) affects cotranscriptional AS in a p53-independent way, through the hyperphosphorylation of RNA polymerase II carboxy-terminal domain (CTD) and a subsequent inhibition of transcriptional elongation, estimated in vivo and in real time. Phosphomimetic CTD mutants not only display lower elongation but also duplicate the UV effect on AS. Consistently, nonphosphorylatable mutants prevent the UV effect. Apoptosis promoted by UV in cells lacking p53 is prevented when the change in AS of the apoptotic gene bcl-x is reverted, confirming the relevance of this mechanism. Splicing-sensitive microarrays revealed a significant overlap of the subsets of genes that have changed AS with UV and those that have reduced expression, suggesting that transcriptional coupling to AS is a key feature of the DNA-damage response.
MeSH term(s)	Alternative Splicing/radiation effects ; Apoptosis ; Cell Line, Tumor ; DNA Damage ; Dichlororibofuranosylbenzimidazole/pharmacology ; Fibronectins/genetics ; Fibronectins/metabolism ; Fluorescence Recovery After Photobleaching ; Humans ; Mutation ; Oligonucleotide Array Sequence Analysis ; Phosphorylation/drug effects ; Phosphorylation/radiation effects ; RNA Polymerase II/chemistry ; RNA Polymerase II/metabolism ; Transcription, Genetic ; Ultraviolet Rays
Chemical Substances	Fibronectins ; Dichlororibofuranosylbenzimidazole (53-85-0) ; RNA Polymerase II (EC 2.7.7.-)
Language	English
Publishing date	2009-01-18
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	187009-9
ISSN	1097-4172 ; 0092-8674
ISSN (online)	1097-4172
ISSN	0092-8674
DOI	10.1016/j.cell.2009.03.010
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Article: Unconstrained mining of transcript data reveals increased alternative splicing complexity in the human transcriptome

Mollet, I.G / Ben-Dov, Claudia / FelÃcio-Silva, Daniel / Grosso, A.R / EleutÃ©rio, Pedro / Alves, Ruben / Staller, Ray / Silva, Tito Santos / Carmo-Fonseca, Maria

Nucleic acids research. 2010 Aug., v. 38, no. 14

2010

Abstract	Mining massive amounts of transcript data for alternative splicing information is paramount to help understand how the maturation of RNA regulates gene expression. We developed an algorithm to cluster transcript data to annotated genes to detect unannotated splice variants. A higher number of alternatively spliced genes and isoforms were found compared to other alternative splicing databases. Comparison of human and mouse data revealed a marked increase, in human, of splice variants incorporating novel exons and retained introns. Previously unannotated exons were validated by tiling array expression data and shown to correspond preferentially to novel first exons. Retained introns were validated by tiling array and deep sequencing data. The majority of retained introns were shorter than 500 nt and had weak polypyrimidine tracts. A subset of retained introns matching small RNAs and displaying a high GC content suggests a possible coordination between splicing regulation and production of noncoding RNAs. Conservation of unannotated exons and retained introns was higher in horse, dog and cow than in rodents, and 64% of exon sequences were only found in primates. This analysis highlights previously bypassed alternative splice variants, which may be crucial to deciphering more complex pathways of gene regulation in human.
Keywords	Primates ; algorithms ; alternative splicing ; cows ; databases ; dogs ; exons ; gene expression ; genes ; genome mining ; high-throughput nucleotide sequencing ; horses ; humans ; introns ; mice ; non-coding RNA ; transcriptome
Language	English
Dates of publication	2010-08
Size	p. 4740-4754.
Document type	Article
ZDB-ID	186809-3
ISSN	0301-5610 ; 0305-1048
ISSN	0301-5610 ; 0305-1048
DOI	10.1093/nar/gkq197
Database	NAL-Catalogue (AGRICOLA)

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